The overall objective of this R21 research plan is to uncover the physiological functions of IL-24, a new cytokine that we recently discovered. IL-24 belongs to the IL-10 family of cytokines. We have identified two heterodimeric EL-24 receptors (IL-22R1/IL-20R2 and IL-20R1 and IL-20R2) which when bound to the ligand leads to STATs activation. Tissue distribution analysis of IL-24 receptor expression indicates that epidermis is one of the major IL-24 target tissues, in contrast to IL-10, which acts mainly on cells from hemopoeitic lineage. We showed that keratinocyres not only expresses IL-24 receptors but also can be activated by IL-24, which leads to mainly StatS activation. Consistently, stat 3 knockout mice were shown to exhibit defects in wound healing. Furthermore, IL-24 expression was found greatly increased during cutaneous wound healing process, and infiltrating mononuclear cells congregating right beneath the wounded epidermis were shown to be the source of IL-24 production. Logically, here we have selected the wound healing process as a model system to explore the physiological functions of IL-24 signaling. We hypothesize that IL-24 may be an important regulator for at least three keratinocyte functions. First, IL-24 produced by infiltrating monocytes may function, in an analogous manner to IL-10 on hematopoietic cells, to inhibit the synthesis of proinflammatory cytokines such as IL-1 and TNF-a by epidermis. In this regard, IL-24 may function as an anti-inflammatory cytokine that signals the attenuation or ultimate termination of inflammatory responses in the skin during the wound healing process. Secondly, IL-24 may function as a signal for keratinocyte proliferation, migration and differentiation during tissue repair. This hypothesis is supported by our finding that IL-24 could substitute IL-3 as a survival and growth factor for murine IL-3 dependent pro-B cells in IL-24 receptor-dependent manner. Thirdly, IL-24 may be part of a more complex cytokine network involved in the wound healing process. We propose the following specific aims to test these hypothesis: Specific Aim 1: To determine the biological functions of IL-24 on keratinocytes by testing if IL-24 can inhibit the production of proinflammatory cytokines, and promote cell proliferation, migration and differentiation. Specific Aim 2: To determine the role of IL-24 in wound healing using mouse skin excision wound model and IL-24 antagonists. [unreadable] [unreadable]